Enantiomerically-enriched chiral primary amines are commonly used as resolving agents for racemic acids, as chiral auxiliaries for asymmetric syntheses and as ligands for transition metal catalysts used in asymmetric catalysis. In addition, many pharmaceuticals, such as sertraline, contain chiral amine moieties. Effective methods for the preparation of such compounds are of great interest to the pharmaceutical industry. Particularly valuable are processes that allow for the preparation of each enantiomer or diastereomer, in enantiomeric or diastereomeric excess, as appropriate, from prochiral or chiral starting materials.
Methods are available for the preparation of enantiomerically enriched amines. For example, the addition of organometallic reagents to imines or their derivatives is reported by Watanabe et al., Tetrahedron Asymm. (1995) 6:1531; Denmark et al., J. Am. Chem. Soc. (1987) 109:2224; Takahashi et al., Chem. Pharm. Bull. (1982) 30:3160; and the addition of organometallic reagents to chiral oxazolidines is disclosed by Mokhallalatiet et al., Tetrahedron Lett. (1994) 35:4267. Although some of these methods are widely employed, few are amenable to large-scale production of amines.
Other approaches involve optical resolution of a single enantiomer or diastereomer from a mixture. Resolution may be conducted through stereoselective biotransformation or by the formation of diastereomeric salts that are separated by crystallization. The utility and applicability of resolution methods relying on selective recrystallization are often limited by the lack of availability of appropriate chiral auxiliaries. In addition, resolution processes upon racemic mixtures afford a maximum yield of 50% for either stereoisomer. Therefore, the resolution of racemic mixtures is generally viewed as an inefficient process.
The preparation of an enantiomerically-enriched amine via conversion of a precursor oxime to the corresponding enamide, which is subsequently converted to the amine through asymmetric hydrogenation and deprotection, has been described (WO 99/18065 to Johnson et al.). The processes are, however, not of general applicability to a wide range of substrates. Moreover, many of the recognized processes require a large excess of metallic reagent to effect the conversion. The result is the generation of significant amounts of solid metal waste, a trait that is undesirable for large-scale production processes.
Therefore, a cost-efficient, scalable method for the conversion of oximes to corresponding enamides, which does not rely on a metallic reagent, is needed. The facile, high yield conversion of readily accessible oximes to the corresponding enamides without the use of metallic reagents would be a valuable step towards the large-scale synthesis of chiral amides and amines. The current invention addresses this and other needs.